US9061996B2 - Solid phase extraction method - Google Patents

Solid phase extraction method Download PDF

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US9061996B2
US9061996B2 US13/993,108 US201113993108A US9061996B2 US 9061996 B2 US9061996 B2 US 9061996B2 US 201113993108 A US201113993108 A US 201113993108A US 9061996 B2 US9061996 B2 US 9061996B2
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aliquot
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US20130261315A1 (en
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Dimitrios Mantzilas
Gry Helene Olaussen
Torild Wickstrom
Eric Horn
Imtiaz Khan
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GE Healthcare Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/84—Separation, e.g. from tar; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles

Definitions

  • the present invention relates to radiochemistry and in particular to a method for the preparation of a radiofluorinated compound.
  • the method of the invention provides a radiofluorination method that comprises purification by solid-phase extraction (SPE).
  • Radioflourinated tricyclic indole compounds are known from WO 2010/109007. These compounds are useful as in vivo imaging agents that bind with high affinity to peripheral benzodiazepine receptors (PBR). The compounds also have good uptake into the brain following administration and good selective binding to PBR.
  • PBR peripheral benzodiazepine receptors
  • Abnormal PBR expression is known to be a feature of a variety of disease states, and in particular disease states comprising neuroinflammation.
  • the PBR selective ligand, (R)-[ 11 C]PK11195 provides a generic indicator of central nervous system (CNS) inflammation.
  • CNS central nervous system
  • (R)-[ 11 C]PK11195 is known to have high protein binding, and low specific to non-specific binding.
  • the role of its radiolabelled metabolites is not known, and quantification of binding requires complex modelling.
  • a radiofluorinated tricyclic indole compound of the type disclosed by WO 2010/109007 is therefore poised to provide an improved PBR selective in vivo imaging agent useful in the diagnosis and monitoring of a variety of disease states.
  • HPLC high-performance liquid chromatography
  • [ 18 F]-radiotracers in particular are now often conveniently prepared by means of an automated radiosynthesis apparatus, e.g. TracerlabTM and FASTlabTM from GE Healthcare Ltd.
  • an automated radiosynthesis apparatus e.g. TracerlabTM and FASTlabTM from GE Healthcare Ltd.
  • FASTlabTM a single-use disposable cassette in which the radiochemistry is performed is fitted to the apparatus.
  • the cassette normally includes fluid pathways, a reaction vessel, and ports for receiving reagent vials and ideally solid phase extraction (SPE) cartridges for post-radiosynthetic clean up steps.
  • SPE solid phase extraction
  • WO 2010/109007 discloses that a preferred method to obtain the radiolabelled tricyclic indole compounds taught therein is by use of an automated synthesiser, wherein purification is preferably carried out by solid phase extraction (SPE).
  • SPE solid phase extraction
  • the present invention provides a method to prepare an 18 F-labelled tricyclic indole compound wherein purification is carried out by solid-phase extraction (SPE) rather than HPLC.
  • SPE solid-phase extraction
  • This method is particularly suitable for carrying out the radiofluorination method on a cassette suitable for use with an automated synthesiser.
  • the present invention provides a cassette designed to carry out the method on an automated synthesiser.
  • halogen or “halo-” means a substituent selected from fluorine, chlorine, bromine or iodine.
  • alkoxy means an alkyl radical comprising an ether linkage.
  • alkyl means a straight-chain or branched-chain radical having the general formula C x H 2x+1 , e.g. methyl, ethyl, and propyl.
  • ether linkage refers to the group —C—O—C—. Examples of suitable alkyloxy radicals include methoxy, ethoxy, ethoxyethyl, and propoxy.
  • methyl refers to the alkyl radical of formula C x H 2x+1 as defined above wherein x is 1.
  • ethyl refers to the alkyl radical of formula C x H 2x+1 as defined above wherein x is 2.
  • benzyl refers to the monovalent aromatic radical C 6 H 5 CH 2 —.
  • An “aromatic” radical is a conjugated hydrocarbon group with a number of ⁇ electrons that equals (4z+2), wherein z is a positive integer or zero (Huckel's rule).
  • the rule applies to hydrocarbons compounds composed of only sp 2 -hybridized carbon atoms.
  • pyrrolidinyl refers to a five-membered aliphatic heterocycle containing four carbon atoms and one nitrogen atom having the molecular formula C 4 H 8 N.
  • An “aliphatic” radical is either acyclic or cyclic and is not aromatic.
  • piperidinyl refers to a six-membered aliphatic heterocycle containing five carbon atoms and one nitrogen atom having the molecular formula C 5 H 10 N.
  • azepanyl refers to a seven-membered aliphatic heterocycle containing five carbon atoms and one nitrogen atom having the molecular formula C 6 H 12 N.
  • morpholinyl refers to a six-membered aliphatic heterocycle containing four carbon atoms, one nitrogen atom and one oxygen atom having the molecular formula C 4 H 8 NO.
  • a “precursor compound” comprises a non-radioactive derivative of a radiolabelled compound, designed so that chemical reaction with a convenient chemical form of the detectable label occurs site-specifically; can be conducted in the minimum number of steps (ideally a single step); and without the need for significant purification (ideally no further purification), to give the desired in vivo imaging agent.
  • Such precursor compounds are synthetic and can conveniently be obtained in good chemical purity.
  • leaving group generally refers to a moiety suitable for nucleophilic substitution and is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage.
  • reaction of the precursor compound with [ 18 F]-fluoride results in the nucleophilic displacement of the sulfonate leaving group from the precursor compound.
  • [ 18 F]-fluoride” refers to the anion 18 F ⁇ .
  • solid-phase extraction refers to the chemical separation technique that uses the affinity of solutes dissolved or suspended in a liquid (known as the mobile phase) for a solid through which the sample is passed (known as the stationary phase or sorbent) to separate a mixture into desired and undesired components. The result is that either the desired analytes of interest or undesired impurities in the sample are retained on the sorbent.
  • the portion that passes through the sorbent is collected or discarded, depending on whether it contains the desired analytes or undesired impurities. If the portion retained on the sorbent includes the desired analytes, they can then be removed from the sorbent for collection in an additional step, in which the sorbent is rinsed with an appropriate eluent.
  • the sorbent is typically packed between two porous media layers within an elongate cartridge body to form a “solid-phase extraction (SPE) cartridge” wherein one or more SPE cartridges may be included in a cassette suitable for use with an automated synthesiser.
  • a typical SPE cartridge comprises a syringe barrel made from medical-grade plastic such as polypropylene that is fitted with a luer tip, with frits holding the sorbent within the syringe barrel.
  • the “sorbent” comprises particles, typically silica-based, to which have been bonded a specific functional group.
  • the sorbent suitably comprises particles having a diameter between 10-120 ⁇ m.
  • the functional groups bonded to the sorbent particles are hydrocarbon chains of variable length. Typical hydrocarbon chain lengths for SPE cartridge sorbents are C2, C8, C18 and C30.
  • conditioning refers to the step of rinsing the SPE sorbent with solvent prior to loading the sample (in this case the reaction mixture).
  • the conditioning step typically comprises application of a water-miscible organic solvent followed by water or an aqueous buffer.
  • reaction mixture refers to the crude product of the reaction between the precursor compound of Formula Ia and the suitable source of [ 18 F]-fluoride.
  • the reaction mixture is not subjected to any other purification steps such as HPLC prior to loading onto the one or more conditioned SPE cartridges.
  • the purifying step is therefore the entire purification process for the reaction mixture.
  • loading simply refers to the application of the reaction mixture to the cartridge, or in the case of more than one cartridge to the first in the series.
  • purifying means the process of separating a desired chemical compound from a mixture that comprises the desired chemical compound along with unwanted chemical compounds.
  • purifying specifically refers to SPE purifying wherein SPE is as defined above; HPLC is specifically excluded.
  • the aim of purifying is to remove as much as possible of the unwanted chemical compounds and as little as possible of the desired chemical compound so that the desired chemical compound is obtained in as high a proportion of the chemical composition of the purified product as possible.
  • the purified product should suitably have a ratio of compounds of Formula Ia:Formula I in the range 20:80 to 0:100.
  • ratios of around 10:90 to 1:99 are aimed for, with ratios in the range 5:95 to 1:99 being preferred.
  • other impurities are removed in addition to precursor compound of Formula Ia.
  • the radiofluorinated compound of Formula I is intended for in vivo use as a positron-emission tomography (PET) tracer, it is necessary to remove any impurities that may have a toxic effect on the mammalian body.
  • PET positron-emission tomography
  • the purifying step should result in the retention of as much radiofluorinated compound of Formula I as possible; suitably ⁇ 75%, preferably ⁇ 90%, and most preferably ⁇ 95%.
  • washing refers to the step of the SPE procedure tailored for the removal of unwanted impurities from the reaction mixture, i.e. in the case of the present invention any chemical compounds in the reaction mixture other than the radiofluorinated compound of Formula I. In particular, it is desired to remove any unreacted compound of Formula Ia.
  • solvent system refers either to a single aliquot of solvent of a particular concentration, or to multiple aliquots of solvent having different concentrations.
  • said first solvent system comprises multiple aliquots of solvent wherein the concentration of water-miscible organic solvent decreases with each successive aliquot.
  • said second solvent system comprises one or more aliquots wherein the concentration of water-miscible solvent is greater than that of any of the aliquots used in the first solvent system.
  • the volume of an aliquot in the context of the present invention can suitably be between 1-50 mL, typically between 5-30 mL.
  • water-miscible organic solvent refers to a solvent other than water that readily forms a homogenous solution with water at room temperature and at atmospheric pressure.
  • suitable water-miscible organic solvents include ethanol, methanol, isopropanol, acetonitrile, dimethylformamide, dimethyl sulfoxide and formic acid.
  • the solvent system could comprise one or more aliquots of 35% aqueous ethanol as well as one or more aliquots of 40% aqueous ethanol and one or more aliquots of 55% aqueous ethanol.
  • eluting refers to the step of the SPE procedure designed to remove the compound of interest (the radiofluorinated compound of Formula I) from the SPE cartridge, but to leave behind any impurities not removed by the washing step.
  • R 1 of Formula I is preferably C 1-3 alkoxy and is most preferably methoxy.
  • R 2 and R 3 of Formula I are preferably both methyl or both ethyl, and most preferably both ethyl.
  • Y 1 of Formula I is preferably CH 2 —CH 2 .
  • n is preferably 2.
  • R 1a of Formula Ia is preferably C 1-3 alkoxy and is most preferably is methoxy.
  • R 2a and R 3a of Formula Ia are preferably both methyl or both ethyl, and most preferably both ethyl.
  • Y 1a of Formula Ia is preferably CH 2 —CH 2 .
  • m is preferably 2.
  • LG of Formula Ia is preferably selected from toluenesulfonic acid (tosylate), nitrobenzenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid (triflate), fluorosulfonic acid, methanesulfonic acid (mesylate) and perfluoroalkylsulfonic acid.
  • LG is tosylate, triflate or mesylate and is especially preferably mesylate.
  • R 1 is C 1-3 alkoxy and preferably is methoxy
  • R 2 and R 3 are either both methyl or both ethyl, and preferably both ethyl;
  • Y 1 is CH 2 —CH 2 ;
  • n 2.
  • R 1a is C 1-3 alkoxy and preferably is methoxy
  • n 2;
  • LG is selected from toluenesulfonic acid (tosylate), nitrobenzenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid (triflate), fluorosulfonic acid, methanesulfonic acid (mesylate) and perfluoroalkylsulfonic acid; preferably tosylate, triflate or mesylate and most preferably mesylate.
  • Said radiofluorinated compound of Formula I is preferably Compound 1:
  • OMs is mesylate
  • the compounds of Formula I and Formula Ia have a chiral centre and been illustrated above as their racemates.
  • the compounds of Formula I and Formula Ia are provided in an enantiomerically pure form, preferably the S-enantiomer.
  • the S-enantiomer of Compound I is as follows:
  • a preferred particle diameter distribution for the sorbent of said one or more SPE cartridges is between 35-120 ⁇ m, more preferably between 35-60 ⁇ m and most especially preferably between 35-55 ⁇ m.
  • the sorbent of the one or more SPE cartridges includes at least some particles having a diameter of between 35-40 ⁇ m, with more preferred sorbents comprising a greater proportion of particles having a diameter between 35-40 ⁇ m.
  • the bonded hydrocarbons of said sorbent have a chain length of C18 or C30.
  • said one or more SPE cartridges used in step (iii) of the purifying step comprise between 300 mg and 3.0 g of sorbent, and most preferably between 1.5-2.0 g of sorbent.
  • the amount of sorbent can generally be provided as 1-3 SPE cartridges, typically two SPE cartridges. For example, in a particularly preferred embodiment, 2 SPE cartridges having 900 mg of sorbent each are provided.
  • Non-limiting examples of commercially-available SPE cartridges that are suitable for use in the purifying step of the method of the invention include e.g.
  • Waters tC18 Sep Pak Plus 900 mg Waters C18 Sep Pak Plus 360 mg, Varian Bond Elute 500 mg, Macherey Nagel C18 ec 530 mg, Princeton C30 950 mg.
  • Preferred of these commercially-available SPE cartridges are the Waters tC18 Sep Pak Plus 900 mg, Varian Bond Elute 500 mg and Princeton C30 950 mg, with the Waters tC 18 Sep Pak Plus 900 mg being most preferred.
  • said water-miscible organic solvent of said first and second water-miscible organic solvent systems is selected from ethanol (EtOH), acetonitrile (MeCN), methanol and isopropanol.
  • the first solvent system comprises one or more aliquots having water:water-miscible organic solvent in a ratio of between 65:35-60:40, i.e. 35-40% aqueous water-miscible organic solvent, wherein each successive aliquot used in the first solvent system has a lower concentration of water-miscible organic solvent, e.g.
  • a first aliquot of 40% aqueous water-miscible organic solvent followed by a second aliquot of 35% aqueous water-miscible organic solvent Preferably, the volume of said first aliquot is greater than that of said second aliquot, e.g. said first aliquot is 20-30 mL and said second aliquot is 5-15 mL.
  • said second solvent system comprises one or more aliquots of aqueous water-miscible organic solvent each having water:water-miscible organic solvent in a ratio of between 60:40 to 0:100, i.e. 40-100% aqueous water-miscible organic solvent.
  • said second solvent system comprises one or more aliquots wherein the concentration of water-miscible organic solvent is greater than that of any of the aliquots in the first solvent system.
  • said second solvent system preferably comprises one or more aliquots having a concentration of water-miscible organic solvent in the range 50-80%, most preferably 50-70% and most especially preferably 50-60%.
  • Said first and second solvent systems may also comprise an aliquot of water as a final aliquot.
  • the most preferred water-miscible organic solvent for said first and second water-miscible organic solvent systems is EtOH.
  • a first aliquot is 40% aqueous water-miscible organic solvent and a second aliquot is 35% aqueous water-miscible organic solvent, optionally followed by a third aliquot of water; and, in said second solvent system a first aliquot is 50-60% aqueous EtOH, optionally followed by subsequent aliquots having EtOH concentration greater than said first aliquot.
  • Non-limiting examples of particularly preferred solvent systems for use in the purifying step of the method of the invention are tabulated below (% values are % water-miscible organic solvent in water, where said organic solvent is preferably EtOH):
  • Solvent System Aliquot # First 1 27 mL 40% 22 mL 40% 2 10 mL 35% 10 mL 35% 3 5 mL H 2 O — Second 1 3 mL 50% 3.5 mL 55% 2 3 mL 65% 3.5 mL H 2 O 3 3 mL 100% —
  • the method of the invention primarily aims to remove as much unreacted precursor compound of Formula Ia from the reaction mixture as possible.
  • the method of the invention also removes additional impurities.
  • the experimental examples demonstrated that the method of the invention removes 90-98% of the precursor compound and 85-90% of a hydroxy impurity and only traces of a vinyl impurity are left.
  • the hydroxy and vinyl impurities are, respectively, as follows:
  • a further notable impurity is the acetyl impurity, which has the following structure:
  • precursor compound of Formula Ia Methods suitable for the preparation of precursor compound of Formula Ia are described in detail in WO 2010/109007.
  • a precursor compound wherein LG is mesylate can be prepared from commercially-available starting materials according to the general method illustrated in Scheme 1 below:
  • R 1a-3a and Y 1a are as suitably and preferably provided herein in respect of Formula Ia.
  • R 5a in Scheme 1 represents CH 2 CwaterBn wherein Bn is benzyl, Et is ethyl, OTs represents a tosylate leaving group, IPA stands for isopropyl alcohol, and OMs represents a mesylate leaving group.
  • [ 18 F]-fluoride is normally obtained as an aqueous solution from the nuclear reaction 18 O(p,n) 18 F.
  • water is typically removed from [ 18 F]-fluoride prior to the reaction, and fluorination reactions are carried out using anhydrous reaction solvents (Aigbirhio et at 1995 J Fluor Chem; 70: 279-87).
  • the removal of water from [ 18 F]-fluoride is referred to as making “naked” [ 18 F]-fluoride.
  • a further step that is used to improve the reactivity of [ 18 F]-fluoride for radiofluorination reactions is to add a cationic counterion prior to the removal of water.
  • the counterion should possess sufficient solubility within the anhydrous reaction solvent to maintain the solubility of the [ 18 F]-fluoride. Therefore, counterions that are typically used include large but soft metal ions such as rubidium or caesium, potassium complexed with a cryptand such as KryptofixTM, or tetraalkylammonium salts, wherein potassium complexed with a cryptand such as KryptofixTM, or tetraalkylammonium salts are preferred.
  • [ 18 F]-fluoride that has been made reactive according to these steps is what is meant in the context of the present invention as a “suitable source of [ 18 F]-fluoride”.
  • [ 18 F]-radiotracers in particular are now often conveniently prepared on an automated radiosynthesis apparatus.
  • apparatus commonly comprises a “cassette”, often disposable, in which the radiochemistry is performed, which is fitted to the apparatus in order to perform a radiosynthesis.
  • the cassette normally includes fluid pathways, a reaction vessel, and ports for receiving reagent vials as well as any solid-phase extraction cartridges used in post-radiosynthetic clean up steps.
  • the method of the invention is automated.
  • the present invention provides a cassette for carrying out the method of the invention on an automated synthesis apparatus, wherein said cassette comprises:
  • the cassette of the invention may furthermore comprise:
  • Example 1 describes the preparation of spiked samples for SPE screening experiments.
  • Example 2 describes the SPE screening experiments.
  • Example 3 describes preparation of decayed FASTLab crude samples for SPE purification experiments.
  • Example 4 describes the SPE purification of Crude 1.
  • Example 5 describes the SPE purification of Crude 2.
  • Example 6 describes the SPE purification of Crude 3.
  • Example 7 describes the SPE purification of Crudes 4 & 5.
  • Example 8 describes the SPE purification of Crude 6.
  • Example 9 describes a number of FASTlab runs that were carried out including SPE purification on the FASTlab cassette.
  • Non-radioactive Compound 1 and Compound 1a were prepared in accordance with the methods described in Examples 2 and 1, respectively, of WO 2010/109007.
  • Amounts of Compound 1 and Compound 1a were estimated based on standard curves generated for Compound 1.
  • FASTLab cassette was assembled with an eluent vial, a QMA cartridge (preconditioned, Waters), a precursor vial and an MeCN vial.
  • the FASTLab samples were prepared by carrying out the FASTLab process up to and including the labelling step, followed by transfer of the crude (approximately 1.3 mL MeCN) to a vial for storage in until analysis.
  • the labelling step was carried out without any fluoride. More detail in respect of each sample is now provided.
  • Samples were prepared for 2 experiments. For each sample, 500 ⁇ L crude (in MeCN) was spiked with 20 ⁇ L Compound 1 solution (1.24 mg/mL in 50:50 H 2 O:MeCN) and then diluted with 1 mL water. 2 mL of each solution was loaded onto the SPE column for the experiments described in Examples 5 and 6.
  • Example 4 The method as described in Example 4 was used for 2 mL of Crude 2 (prepared as described in Example 3) except that elution was carried out using 3 mL of 50% aq EtOH, 3 mL of 60% aq EtOH, 3 mL 70% aq EtOH and 3 mL of 80% aq EtOH were used.
  • Example 5 The method as described in Example 5 was used to purify 2 mL of Crude 3 (prepared as described in Example 3) except that the 3 mL 50% aq EtOH step was changed to a 3 mL 40% aq EtOH step, and followed by 3 mL of 65% aq EtOH and 3 mL of 100% EtOH.
  • the wash with 3 mL of 50% aq EtOH removed another 35% of the hydroxy and small amounts of Compound 1a.
  • the 3 mL of 65% aq EtOH contained 50/50 Compound 1/hydroxy and traces of Compound 1a and vinyl. This means that approximately 85-90% of the hydroxy was removed during the procedure.
  • the vinyl impurity is mainly trapped on the cartridge and eluted out with 100% EtOH.
  • Crude 5 contains almost double ⁇ gs of Compound 1a compared to Crude 4, but the results are comparable. The method was able to remove nearly all Compound 1a in both crudes.
  • the ratio given in the table is based on the area under the peak at 230 nm.
  • the lowest values included in the standard curve were 0.115 ⁇ g.
  • a FASTlab process was carried out for the production of a number of batches of the S-enantiomer of Compound 1.
  • Up to 80 GBq of [ 18 F]fluoride obtained from a GE PETrace cyclotron (from H 2 18 O) was introduced into the FASTLab synthesiser (GE Healthcare), and trapped on the QMA cartridge.
  • Approximately 475 ⁇ l eluent solution (KHCO 3 +kryptofix in MeCN/water (80/20, v/v) was used to elute the [ 18 F]fluoride off the QMA cartridge into the reaction vessel.
  • the material in the reaction vessel was then dried at 120° C. for 9 minutes followed by transfer of 4.0 mg of Compound 1a dissolved in 1.6 mL MeCN to the reaction vessel. Labelling was carried out at 100° C. for 6 minutes.
  • reaction mixture was applied to the first in a series of 2 conditioned 900 mg Waters tC18 SPE cartridges in situ on the FASTlab cassette and the SPE purification process was carried out as follows: a first solvent system comprising 22 mL 40% EtOH followed by 10 mL 35% EtOH and a second solvent system comprising 3.5 mL 55% EtOH and 3.5 mL water.
  • FIG. 1 provides details of the runs that were carried out, including initial activity, uncorrected end of synthesis (UEOS) yield, radioactive concentration (RAC), radiochemical purity (RCP), as well as the amounts of each compound (all S-enantiomer compounds) separated in the SPE process. RCP values in excess of 95% were routinely achieved.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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US12162009B2 (en) 2018-03-29 2024-12-10 Ge Healthcare Limited Solid phase purification

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